We propose to develop a birth control vaccine for women that blocks fertilization and is effective, safe and widely acceptable. PH-20, a sperm surface protein shown to give 100% effective contraception in one animal model (guinea pig), is currently our primary candidate antigen. We are testing PH-20 immunogenicity in monkeys and anticipate that immunization of female monkeys with PH-20, under optimal conditions, could give fully effective contraception. Given this result, we will pursue commercial development of a PH-20 based vaccine. We also propose to continue to study other sperm antigens that might eventually be used with PH-20 in a second generation vaccine. (A second generation vaccine might have longer duration, fewer doses, lower cost or other advantages). Also, other sperm antigens can be developed as alternatives to PH-20, if PH-20's development stalls. One alternative antigen is fertilin which functions in sperm-egg binding and fission and has a known- active site. We will test contraceptive efficacy of immunizing female monkeys with the active site region of fertilin. Other candidate antigens, sp56 and CRISP-1 (DE), will first be screened by gene knockout to determine if they have an dispensable role in fertilization. If the gene knockout produces mutant male mice that are completely infertile, the protein (sp56 and/or CRISP-1) will be definitively identified as a contraceptive target and developed as an immunogen. Thus, a collection of antigens will be available whose contraceptive efficacy can be evaluated singly and combined.